Novel therapeutics and treatment regimen in wound healing

Abstract

Since antiquity, wounds have inflicted enormous pain and suffering to mankind. Amelioration of this pain, faster healing was a daunting task for us from ancient times. The process of wound healing is complex and tightly regulated which mainly affect certain tissues of the bodyprimarily including the skin. It is of paramount importance as it concerns reinstating the integrity of the skin tissues. The cascade of recovery of the wounds may be affected due to a plethora of disease processes, which is further known to induce considerable distress and perturbation to the patients. Medical science has been keen on understanding the mechanism of wound healing and has used many medicaments to help reduce the duration of relapse or recovery. The treatment methods span from the usage of many phytoconstituents to the modern regimen of using novel formulations. The aim of this article is therefore to review the recent biotechnological interventions along with novel treatment regimen that have been devised over the years and pose great potential for the effective treatment of a multitude of wounds.

Full text

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International Journal of Herbal Medicine 2021; 9(1): 12-18
E-ISSN: 2321-2187
P-ISSN: 2394-0514
www.florajournal.com
IJHM 2021; 9(1): 12-18
Received: 29-10-2020
Accepted: 08-12-2020
Ryan Varghese
Bharati Vidyapeeth Deemed
University, Poona College of
Pharmacy, Pune, Maharashtra,
India
Vaibhav Shinde
Bharati Vidyapeeth Deemed
University, Poona College of
Pharmacy, Pune, Maharashtra,
India
Corresponding Author:
Ryan Varghese
Bharati Vidyapeeth Deemed
University, Poona College of
Pharmacy, Pune, Maharashtra,
India
Novel therapeutics and treatment regimen in wound
healing
Ryan Varghese and Vaibhav Shinde
Abstract
Since antiquity, wounds have inflicted enormous pain and suffering to mankind. Amelioration of this
pain, faster healing was a daunting task for us from ancient times. The process of wound healing is
complex and tightly regulated which mainly affect certain tissues of the bodyprimarily including the skin.
It is of paramount importance as it concerns reinstating the integrity of the skin tissues. The cascade of
recovery of the wounds may be affected due to a plethora of disease processes, which is further known to
induce considerable distress and perturbation to the patients. Medical science has been keen on
understanding the mechanism of wound healing and has used many medicaments to help reduce the
duration of relapse or recovery. The treatment methods span from the usage of many phytoconstituents to
the modern regimen of using novel formulations. The aim of this article is therefore to review the recent
biotechnological interventions along with novel treatment regimen that have been devised over the years
and pose great potential for the effective treatment of a multitude of wounds.
Keywords: Wound, wound healing, wound dressing
1. Introduction
The human skin is regarded as the single largest organ of the human body and characterizes its
first line of defense. It is primarily concerned with the protection of the human body from
various mechanical stresses and pressure. It also confines the leverage of variations in physical
constants like temperature, atmospheric pressure, and humidity [1]. Thus the skin is such a vital
organ, the integrity of the skin has to be restored by a series of physiological processes that
have been targeted to repair the impaired tissues. The skin wound is portrayed by an injury
made on the skin due to a plethora of conditions including trauma, laceration, abrasion, or
contusion [2]. The wound healing and scar formation are highly maintained physiological retort
to wound formation in most tissue, oftentimes the cutaneous tissues, in a preponderance of
higher organisms, which occurs in a corollary of well-characterized stages. These stages may
be categorized into Inflammation, Proliferation, and Remodeling, which are targeted to heal
and repair the affected tissues and also to reinstate their routine functions. Seldom owing to a
plethora of physiological phenomena, this sequence can also be disturbed, and thus may also
come to a standstill before completion, which further results in many undesirable resultants
spanning from the formation of a large local scar to organ-circumfusing fibrosis. These
processes or outgrowths are generally recognized to cause a lot of cosmetic exasperation and
botheration to the individual. These might also pave ways to significantly diminish the loss of
function or ability of the tissue and may turn out to chronic non-healing wounds as in the case
of ulcers which include venous, arterial, diabetic, pressure, and traumatic ulcers [3].
2. Novel approaches to accelerate wound healing
Faster wound healing is an interplay of plethora of physical, chemical, biological, and
microbial factors with an interdisciplinary bridge that help counteract the parameters which
delay the healing of wounds.
The most evident factors showing a profound effect on wound healing primarily includes:
2.1 Wound healing by dermal grafts
The usage of Dermal grafting has been a method of choice in a variety of therapies for ages
altogether. It has been successfully employed in the treatment and complete cure for both acute
and chronic wounds, with the lowest number of morbidities arising as a side-effect and
optimum efficacy achieved in the shortest period. This is employed in the treatment of chronic
wounds, with an intent to attain complete closure of the wound with the functional
regeneration of the injured tissue, contrary to the acute wounds which are done to enhance the
aesthetic outcome of a wound using a Full-Thickness wound graft (FTSGs), in the affected

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area. The rationale of the regenerative efforts is to diminish
the skin defects, these autologous grafts aid as both tissue
substitutes and also provide a pharmacological incentive for
the recuperation of the wound [4].
The treatments using the grafts are enhanced using the skin
flaps which are estimated to bring about more textural
durability and contracture, and thereby reducing the
complexity of the surgical procedure and the complications
arising thereafter, and can be achieved by reducing the
duration of hypoxia and consequent ischemia and also
increasing the blood supply to the grafted flap and thereby
increasing innervation of oxygen permeability to the tissues.
This further reduces the ischemic time for the tissues and the
skin grafts thus have quality at par with the flaps in
precocious points after the transplantation [5].
The efficacy of the flaps can be exponentially increased by
the exposure of the patient to a novel technique popularized as
the Hyperbaric Oxygen Therapy (HBOT), where the patients
daily were made to breathe 100% oxygen through a mask at
an absolute pressure of 2-5 atmospheres during four sessions
for a total duration of 85 minutes [6].
Table 1: Factors influencing Wound Healing
Local variables
Systemic variables
Medication therapy
Pathological variables
Site of Injury
Age
Non-Steroidal Anti
Inflammatory Drugs
Diabetes
Impact of Injury
Gender and Sex Hormones
Chemotherapeutic Agents
Genetic or Hereditary Skin Healing Disorders
Infection
Psychological Stress
Radiation Therapy
Obesity
Vascular Oxygenation
Nutrition
Steroidal Drugs
Immunocompromised Conditions (AIDS, Cancer)
Mechanical Stress
Alcoholism and Smoking
Habits
Cholesterol-Lowering
Agents
Keloids or Fibrosis
Irritants
Immobility
Glucocorticoid Steroids
Jaundice or Uremia
2.2 Wound healing by hydrogel formulations
Hydrogels are currently regarded as the most efficacious
method of wound healing as in cases of both acute and
chronic wounds, with little or no side effects and are cogitated
to be a potential breakthrough in the very nearer future. These
formulations are capable of retaining a damp and moist
environment in limits of the injured area, being permeable to
gases exchange through the material, and also acting as a skin
substitute that resists infection by the pathogens and
absorbing the exudate. This can also be removed with great
ease and is known to be innocuous to the healing tissues. The
injectable hydrogels are known to have an added benefit to
encapsulate certain drugs in situ, thereby filling the wounds
even at the irregular areas and thereby strongly clinging on to
the injured tissues [7].
There is a multitude of hydrogel formulations that are
currently employed in the treatment of a plethora of wound
injuries, ranging from acute to chronic, and from abrasions to
burn injuries. It is therefore of paramount importance that
these formulations are having a great anti-bacterial activity to
avoid any chances of septicity. Many hydrogels are
formulated using Chitosan which is known to possess inherent
antibacterial activity alongside certain other advantages
including pronounced analgesic effect and haemostatic
activity. In addition, the Quaternized chitosan-g-polyaniline
copolymer exhibits enhanced water solubility, antibacterial
activity, and cytocompatibility, suggesting its stellar
performance to prepare an antibacterial injectable hydrogel
wound dressing [8].
The novel new-generation hydrogel that has been used for
potential applications in the wound dressing possesses self-
healing ability and mechanical toughness, with the potential
to cure both the skin as well as the muscle damage and thus,
has been employed in the treatment of not only primary and
secondary but also tertiary degree bruises and wounds. The
self-healing ability of the hydrogel is obtained through the
hydrogen linking and dynamic Schiff cross-linking between
Dopamine Grafted Oxidized Sodium Alginate (OSA-DA) and
Poly-Acrylamide (PAM) chains. This covalent cross-linking
is calculable for its stable mechanical armature. This unique
compilation of both physical and chemical cross-linking
contributes to the novel self-healing ability (80% mechanical
recuperation in 6 hours), high tensile strength (0.109 MPa),
and ultra-stretchability (2550%) which are highly preferred
for wound dressing purposes. Owing to the abundance of
Catechol groups on the OSA-DA chains, this formulation is
known to delineate immense cell affinity and tissue
adhesiveness, marking a potential refinement in the wound
treatment [9]. The smart-materials, which are thought to
instinctively respond to the dynamic inner-state variables of
the living tissues are currently the topic of great interest, to
develop self-adapting solid materials that can automatically
change their orientation, without the influence of any external
stimulus, which is conferred by the unique mobility of the
solid-gel owing to the self-adapting property of the chitosan-
based self-healing hydrogel and the Schiff base network,
among the many others that are currently being studied [10].
2.3 Wound healing by employing growth factors
The usage of several growth factors can help trigger some of
the most essential agents which are vital in the healing
process which includes pivotal roles like neovascularization
and cell migration and additionally may eliminate some of the
harmful ones like fibrosis, which may have a deleterious
effect on the wound and the dermal barrier as a whole. The
key players in these include the multitude of growth factors
including Transforming Growth Factor- (TGF-), Fibroblast
Growth Factor (FGF), Epidermal Growth Factor (EGF),
Vascular Endothelial Growth Factor (VEGF), Platelet-
Derived Growth Factor (PDGF), and Interleukins like
Interleukin-1 (IL-1), Interleukin-6 (IL-6) and Interleukin-8
(IL-8), which aid in proper and efficient wound regeneration
naturally and synthetically producing advanced skin
substitutes [11]. Of the numerous growth factors essential for
wound regeneration, we may focus on some really important
ones.
2.3.1 Transforming Growth Factor- (TGF-)
The Transforming Growth Factor- is a homodimeric protein,
of about 25 kilodaltons (kDa) and plays a plentitude of
biological functions and has a profound effect on the
epithelium-derived and mesenchymal-derived cells [12]. There
are mainly three types of TGF-s which are studied for a
significant role in wound healing, namely TGF-1, TGF-2,

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and lastly TGF-3. The embryonic wounds that heal without
forming any scars are observed to express low levels of TGF-
1 and TGF-2, but a significantly high level of TGF-3, in
contrast to the adult scarring wounds which express a high
level of TGF-1 and TGF-2 and a lower amount of TGF-3
(11). Although, the effect of TGF- on wound healing and
regeneration is quite complicated, but is strongly believed to
stimulate collagen production in the dermal fibroblasts by a
process of fibroblast-to-myofibroblast transition [13]. The
TGF- is often associated with the inhibition of the epidermal
keratinocyte proliferation and growth, although an excess of
the latter would increase the cellular rigidity which would
result in protrusions and keloid formation [14]. A study
including the small compounds that suppressed type-I
collagen production in fibroblasts has observed HSc025,
which antagonizes the TGF-/Smad signal, significantly
accelerated the healing of the wound in mice models,
particularly by the modification of the infiltration,
proliferation, and migration of the various cellular and tissue
components [15]. Therefore, it shows that TGF-, possibly
functions as a pleiotropic modulator in this process, and its
subsequent alterations in adjunct to dermal substitutes may
prove as a gold standard to heal wounds with negligible
fibrosis, which still is not completely achieved by the current
treatment regimens.
2.3.2 Fibroblast Growth Factor (FGF)
The Fibroblast Growth Factor (FGF) is considered to
contribute to the wound healing process by primarily
improving the angiogenesis, and also by cell migration and
proliferation to some extent. The Fibroblast Growth factor-2
(FGF-2), also deemed as the basic FGF (bFGF), is correlated
with the neovascularization and subsequent thickening of both
the dermis and epidermis [16]. Furthermore, it is attributed to
preventing the contraction of the wound through inhibition of
the actin filaments of -smooth muscle, and additional
fibrosis reduction by preventing fibroblast differentiating into
myofibroblasts [17]. Thus, this factor provides controlled
angiogenesis in the wound, therefore breathing life into the
newly formed tissue.
2.3.3 Epidermal Growth Factor (EGF)
The Epidermal Growth Factor (EGF) enhances wound healing
and regeneration by their pronounced action on enhancing
migration and proliferation of the keratinocytes and
fibroblasts. Additionally, they prove as an aid in angiogenesis
and epithelialization [18]. They indirectly trigger the growth
factor secretion produced by the fibroblasts, thus further
accelerating the wound healing (19). The Endothelial Growth
Factor Receptor (EGFR) and Endothelial Growth Factor
(EGF) – like peptides are often over-expressed in human
carcinomas and have a profound ability to induce cellular
transformations, as suggested by numerous in-vitro and in-
vivo studies [20]. Research including the utilization of
Epidermal Growth Factor (EGF) and an EGF family member,
Neuregulin (NRG-1), whose cellular role is in the promotion
of proliferation and migration in fibroblasts and keratinocytes
into a wound site during the primordial steps of skin
regeneration, induced rapid proliferation of skin cells in an
ERK pathway-dependent manner and exhibited efficient
wound healing in Sprague-Dawley rat full-thickness excision
and grafting model. These results provide the foundation for
expanding the growth factor functionalized grafts to clinical
applications in cases of severe skin injuries [21].
2.3.4 Vascular Endothelial Growth Factor (VEGF)
The Vascular Endothelial Growth Factor (VEGF) is the major
growth factor responsible for angiogenesis, which is defined
as the phenomenon involving the growth of new blood vessels
from the pre-existing ones [22]. The VEGF protein tyrosine
kinase receptors have been proved to show its expression on
endothelial cells, including VEGFR1 (alternatively known as
Fms-like tyrosine kinase-1) and VEGFR2 (alternatively
known as fetal liver kinase-1 or kinase insert domain-
containing receptor) [23]. But it is also to be kept in notice that,
higher levels of VEGF may be potentially related to numerous
cancers, fibrosis, the formation of scars, and microvascular
defects in patients diagnosed with diabetes [24].
2.3.5 Platelet-Derived Growth Factor (PDGF)
The Platelet-Derived Growth Factor (PDGF) is involved in a
multitude of growth processes, which during embryogenesis
plays a pivotal role in the vascular development by
stimulating the proliferation and survival of the vascular
mural cells, in contrast to that in adults where it is proven to
be a potent mitogen and survival factor for fibroblasts and
other mesenchymal cells [25]. The Platelet-Derived Growth
Factors (PDGFs) were discovered for more than two decades.
The PDGF family consists of five different disulfide-linked
dimers built up of four different genes. These isoforms,
PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-
DD, act by employing two tyrosine kinase receptors namely
PDGF receptors  and  [27]. The potential clinical application
of PDGF is a potent agent to improve the tissues deficient in
wound repair. Additionally, a thorough understanding of
PDGF may also permit the development of specific
antagonists to limit its effect in many proliferative diseased
conditions [27].
2.4 Wound healing by stem cells
During the proliferative phase of the wound healing
procedure, there is a dire need to increase the total epithelial
cell count to indemnify for the lost cells, to achieve successful
re-epithelialization. Excessive renewal over the differentiation
can easily be accomplished by increasing the proportion of
the cells that undergo differentiation. The same principle has
been exploited in the stem-cell therapy as observed in a
multitude of experiments including, when the stem cells from
the hair follicle or the infundibulum were engaged upon the
injured tissue, they gradually lose their initial identity and get
reprogrammed to differentiate to the epithelial wound tissue
[28].
This treatment regimen has been tested for more than a
decade on various conditions, especially in complex cases of
burns and diabetes, where the repair process is not considered
sufficient to achieve a concrete remedy, in which the resultant
is neither aesthetically nor functionally complete. Although
the epidermal stem cells in the basal layer that act as an
endogenous source of stem cells are potent enough to
regenerate the skin, these are not ample enough to provide an
accurate repair after intensive skin damage. Thus, this therapy
may be regarded as a novel therapeutic strategy as it employs
an exogenous supply of undifferentiated stem cells in such
traumatic conditions [29].
The current interest of a multitude of scientists and
researchers across the globe, is to find out sources of stem
cells that help in the re-epithelialization of the wounds and the
injured tissue and which proliferates, differentiate, and is
known to survive for a long term and barely targets a
committed progenitor population. The stem cells that have

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been used in an experiment conducted by Mascré et al. (2012)
included the usage of Keratin 14 which is known to target
basal cells of the epidermal tissue also including a progenitor
population that proliferates and differentiates and Involculin
which only targets a committed progenitor population. Both
of these populations were employed at the wounded area, but
it was predominantly found that the progenies of Keratin 14
expressing cells survived the long term, in contrast to the
progeny of Involculin expressing cells that were lost earlier.
This study sheds light on the significance of the relatively
undifferentiated cells in the basal layer of the dermal
epithelium, and their contribution to wound healing after
injury [30].
A lot of research is also being conducted concerning the
utilization of Mesenchymal Stem Cells (MSCs), Embryonic
Stem Cells (ESCs), and Induced Pluripotent Stem Cells. The
harnessing of the adult Mesenchymal Stem Cells (MSCs)
avoids the ethical concerns regarding the fetal tissue harvest
as in the case with the embryonic-derived tissues. to date have
been successfully isolated from a plethora of sources
including the Bone Marrow, Umbilical Cord Blood,
Wharton’s Jelly, and Adipose Tissues, where its origin plays a
major determinant of the progenitor characteristics. These
have been tested for their efficacy in a multitude of models
like the adipose tissue-derived MSCs has proven efficacy to
facilitate chondrogenesis possesses substantial osteogenetic
potential in rabbit condylar defect model and murine calvarial
defect model. Bone-marrow derived MSCs have proven to
differentiate into a broad spectrum of non-hematopoietic cells
and consequently produce many Growth Factors and
Cytokines considered pivotal for tissue repair and remodeling
and are currently being evaluated through clinical trials as the
remediation of Chronic Obstructive Pulmonary Disorder
(COPD), with varying inclusion criteria (varied stages of
COPD). Thus, marking this therapy as a novel treatment for
wound healing and remodeling [31].
2.5 Wound Healing by hyperbaric Oxygen Therapy
(HBOT)
The HBOT has been successfully proposed in a multitude of
ailments ranging from Influenza to carcinomas, since its
clinical recognition in 1956. Hyperbaric Oxygen Therapy
(HBOT) is a treatment regimen where the patients breathe
100% oxygen gas inside a hyperbaric chamber that is
pressurized to more than that of sea level (absolute 1
atmosphere) using a face mask, hood, or an endotracheal tube.
For optimum clinical efficacy, the Undersea and Hyperbaric
Medical Society (UHMS) standardizes the pressure to more
than 1.4 ATA; but in clinical practice, applied pressure ranges
from 2 to 3 ATA. In wound healing the protocol invariably
adjunct to the standard wound care treatment typically
constitutes HBOT Treatments of 1.5-2 hours per treatment
and can also go up to 60 treatments. It is most likely for
patients to portray better outcomes when treated with HBOT
as early as possible following an embolism formation [32]. It is
also currently employed as the treatment of choice in atypical
wounds comprising Diabetic Foot Ulcers (DFUs) in wounded
patients with certain other comorbidities like diabetes. The
administration of hyperbaric oxygen increases the systemic
oxygen concentration to as high as 2000 mmHg, whereas
under normal conditions the tissue oxygen concentration
usually ranges from 200 mmHg to 400 mmHg [33]. The HBOT
exploits the principle that the Systemic Hyperoxygenation
initiates the generation of Reactive Oxygen Species (ROS)
and Reactive Nitrogen Species (RNS), which in turn
stimulates the cascade of increased synthesis of wound
growth factor alongside stem cell mobilization which
consequently increases the deposition of collagen fibers and
fibroblast proliferation. Of all the wound growth factors, the
most notable is the Vascular Endothelial Growth Factor
(VEGF), which is primarily associated with
neovascularization, which increases by about 40% under the
hyperbaric conditions. The consequent result is the
neovascularization in the injured tissues along with the added
benefit of the decreased systemic inflammatory response in
the compromised tissue [34]. There also exists another
convergent mechanism of action of the HBOT as it is
proposed for the treatment of carcinomas and associated
wound healing, which departs from the notion of sequential
tissue healing stages by activating a cascade of events or
waves pertaining to ROS, RNS, Lactate, and Nitric Oxide.
Furthermore, it is believed to have effects on several cell
signaling events that converge to influence cell recruitment/
chemotaxis and gene regulation/protein synthesis responses
which mediate wound healing [35]. This is still believed to be a
treatment method for a multitude of disorders especially
wound healing as it ensures that the patients obtain safe,
effective, and economic treatment in chronic wounds. This
currently serves as an arena to be thoroughly explored by the
clinicians and researchers as there currently is a lack of
clinical trials and advanced studies on the other causes of
chronic wounds [36].
2.6 Wound healing using Negative Pressure Wound
Therapy (NPWT)
The NPWT is a recent intervention in the field of wound
therapy that has proven efficacy to promote healing, and also
to reduce the rates of amputation in patients suffering from
wounds or in cases of patients with wounds having certain
comorbidities like those with Diabetic Foot Ulcers (DFUs).
Sometimes, this is unambiguously also addressed as Vacuum-
Assisted Wound Closure (VAWC). It is currently accepted as
a treatment regimen in wound care and is promoted for use on
complex wounds, as an adjunct to the standard care or
therapy. It majorly employs the usage of a wound dressing
through which a negative pressure or vacuum is applied and
the suction created helps in the evacuation of the wound and
the tissue fluid from the compromised area, directly into a
canister. Although this intervention was developed in the
1990s, it’s acceptance and usage has been humongous over
the past few years. The US Department of Health and Human
Services in 2009 had reported that the Medicare payments
from 2001 to 2007 for the NPWT surged from USD 24
million to a phenomenal USD 164 million showing an
increase of nearly 600% [37].
The therapy employs the usage of suction pressure, although
the amount of pressure used can vary and there is no finite
protocol to use, however under the clinical conditions, the
applied pressure varies from 75 mmHg to 150 mmHg, with
125 mmHg being the one most commonly used. The NPWT
market has certainly grown over the last decade, with the
machines becoming more small, compatible, and portable, the
most advanced machines also introduced the concept of
‘single-use’ or ‘disposable’ negative pressure products (for
instance, PICO: Smith & Nephew, UK). Ad hoc, non-
commercial, negative pressure devices are also known to be
used in resource-deprived settings. These devices are
generally known to employ the simple and more primitive
wound dressings, such as gauze, or transparent, occlusive
(non-permeable) dressings, with a negative pressure being

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generated in the hospital by vacuum suction pumps. The
NPWT has now been employed by a multitude of health care
professionals for use in both primary and secondary
community care, especially following the introduction of
ambulatory systems [38].
The NPWT therapy aids in wound healing by collecting the
high volumes of exudates, thus reducing the frequency to
change the dressings especially in cases of anatomically
challenging wounds as in cases of wounds pertaining to the
patients with comorbidities like diabetes mellitus and accident
wounds. Consequently, this also helps keep the wound clean
and reduces odour. The therapeutic efficacy of the therapeutic
regimen is believed to be because the application of
mechanical force onto the wound provides biologically
credible processes that promote the wound healing process
mainly by the drawing together of the wound edges, enhanced
perfusion, and the removal of infectious material and exudate
[39]. This is still being a subject of thorough study and much
interest of researchers and clinicians as they are still trying to
understand the molecular effects of negative pressure on the
wound bed [40].
2.7 Wound healing using Bio-Glass therapy
Biomaterials are undoubtedly one of the most critical factors
that play a pivotal role in the field of tissue engineering. It has
been widely recognized that bioactive materials have a great
influence on cellular behaviours during the processes of tissue
engineering. Bioglass (BG) is a bioactive silicate material,
which is the first man-made inorganic material used in the
engineering of bone tissue, because of its pronounced
osteostimulatory ability. In the last decade, Bioglass has been
employed in the engineering of soft tissues as well. Bioglass
constitutes of Silicon Oxide (SiO2), Sodium Oxide (Na2O),
Calcium Oxide (CaO), and Phosphorous Pentoxide (P2O5) in
specific proportions, and the reactions that take place on the
surface of the Bioglass stimulates the release of soluble ions
primarily comprising Si, Ca and P [41].
During some extensive in vitro studies, the Bioglass ion
extracts prevented the death of the Human Umbilical Vein
Endothelial Cells (HUVECs) following a case of hypoxia in a
proportional dose-dependent manner, possibly through the
connexin hemichannel modulation. BG also proved to show
stimulatory effects on the gap junction pertaining between the
HUVECs and also upregulated the Connexin 43 (Cx43)
expression. Additionally, BG also stimulated the expression
of Vascular Endothelial Growth Factor (VEGF) and also the
basic Fibroblast Growth Factor (bFGF) as well as their
receptors, and Vascular Endothelial Cadherin in HUVECs, all
of which are known to play key roles in the vascularization of
the granular tissue [42].
The Bioglass formulations are estimated to have room for
infinite possibilities due to the varying concentrations of the
constituting inorganic components, and slight variation in
their concentrations may elicit a spectrum of therapeutic
outcomes. They also possess the ability to be formulated into
various medicaments having chemical constituents containing
proven pharmacophores instilled into the formulation [43].
Several such medicaments are currently being produced, one
such is the ones containing gold nanoparticles (AuNPs) as the
gold can increase the rate of wound healing including the
regeneration of tissue, the formation of connective tissues
and, angiogenesis [44]. The Bioglass has also been studied by
building an inter-therapeutic regimen that primarily merges
the hydrogel therapy and Bioglass formulation, where the
Bioglass resembles a hydrogel that encapsulates drug moieties
in a Human Serum Albumin (HSA) carrier. This is an ideal
carrier for drug delivery being the most abundant plasma
protein, its biodegradability, lack of toxicity, and
immunogenicity. This has been referred to as a potential
biomaterial in recent years. There is a plentitude of studies
that show that the free amino side chains of lysine residues on
albumin surface can bond with poly (ethylene glycol)
disuccinimidyl succinate (PEG-(SS)2) to form amide linkages
which consequently result in the formation of hydrogel
materials [45]. Certain studies also show that the succinimidyl
active esters have the potential to react with the amino groups
that are present on the tissue surface, which can result in the
adhesion of these hydrogels on tissues [46]. The therapy is also
believed to alter the cell therapy and tissue engineering by
acting as a reservoir of bioactive silicates which have proven
ability to initiate the paracrine effects between the stem cells
and the recipient cells, which entirely defines the ability of the
regeneration of tissue by the stem cells in the cell therapy.
Thus, it is also regarded as a therapy which is believed to
have tremendous prospects [47].
3. Recent advancements and clinical trials in wound
healing
The list of all the active clinical trials on the novel therapies
of wound healing is appended as follows with a reference to
and was compiled as “Wound healing” on the official website
“clinicaltrials.gov” and “PubMed”.
Table 2: Recent clinical trials in wound healing
Sr. No.
Name
Condition
Intervention
Status
Reference
1.
Cold Plasma Therapy for Acceleration of
Wound Healing in Diabetic Foot
 Diabetic Foot
 Device: Argon Plasma Jet
 Device: Placebo
Active
NCT04205942
2.
Safety and Efficacy of SLI-F06 in Wound
Healing and Scar Appearance
 Scars
 Drug: SLI-F06
 Drug: Formulation Buffer
Active
NCT03880058
3.
Allograft Reconstruction of Massive
Rotator Cuff Tears vs Partial Repair
Alone
 Rotator Cuff
Syndrome
 Rotator Cuff Injury
 Disorder of Rotator
Cuff
 Procedure: Partial Rotator Cuff Repair
 Procedure: Partial Rotator Cuff Repair
with Allograft Augmentation
Active
NCT01987973
4.
ACell MatriStem Pelvic Floor Matrix vs
Native Tissue Repair (Comparative
Study)
 Pelvic Organ
Prolapse
 Device: MatriStem Pelvic Floor
Matrix
 Procedure: native tissue repair
Active
NCT02021279
5.
G-Wound (VZ for Wound treatment)
 Wounds
 Wound Heal
 Device: VZ powder (purified
clinoptilolite)
 Procedure: Standard of care (SoC)
Active
NCT04417647
6.
Prospective Randomized Clinical Trial
comparing outcomes of secondary
 Wound Surgical
 Wounds Heal
 Procedure: Debridement
Active
NCT03880331

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International Journal of Herbal Medicine http://www.florajournal.com
Intention Wound care Methods
7.
Investigation of a Novel Wound gel to
improve wound healing in chronic
wounds
 Wound Infection
 Drug: Benzalkonium Gel
 Other: standard of care topical gel
 Procedure: Debridement
Active
NCT03686904
8.
Efficacy of Continuous Sciatic Nerve
block in Diabetic Foot Patients
 Diabetic Foot
 Wound Heal
 Procedure: Group C (Continuous
sciatic nerve block)
 Procedure: Group S (sciatic nerve
block)
Active
NCT04212325
9.
Healing Chronic venous stasis wounds
with autologous cell therapy
 Wound,
Nonpenetrating
 Device: Transpose ® RT System
 Other: debridement/dressing of the
wound
Active
NCT02961699
4. Conclusions
Wounds have created significant emotional, functional trauma
to patient and at the same time heavy burden on healthcare
professionals. Still, wound healing is one of the underrated
research area which need more emphasis. Over the course,
nature and cause of wounds have changed but it problem
continues to scare the mankind. Last two decades have
witnessed a sea of changes resulting metamorphosis in our
understanding, knowledge, techniques and technologies. It is
a very unfortunate to have wounded lesions, especially in
cases including chronic wounds, however the normal
physiological mechanisms are always working round the
clock to reinstate the normal anatomical and physiological
barrier, particularly because of the pivotal role it plays in the
body. However, the time it takes for reinstating depends upon
numerous factors and can be delayed by various pathological
states, and thus there are numerous effective approaches
employed by the cosmetic surgeons and physicians to
accelerate the process and enhance the patient compliance to
the regimen. The most recent advances in the same included
the aforementioned therapies, which can be used to treat the
cases involving wounds which would naturally take a
prolonged duration to heal and often end up with scars. In
coming years, the acceptance of these and another newer
biotechnological modalities will create room for better and
compliant treatment across the globe.
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